Dorsal root ganglion (DRG) neurons from fetal trisomy 16 mice, a model for trisomy 21 (Down syndrome) in humans, were shown in tissue culture to have altered electrical properties compared to control neurons. Trisomy 16 neurons displayed action potentials with elevated rates of depolarization and repolarization, resulting in reduced spike duration. These differences were essentially identical to abnormalities observed in fetal trisomy 21 neurons. Trisomy 19 DRG neurons showed no differences in passive or active membrane properties compared to normal cells. DRG neurons transgenic for the human gene for superoxide dismutase showed no significant differences in action potential parameters compared to control cells, indicating that excess dosage of this gene alone does not underlie abnormalities identified in trisomy 16 or trisomy 21 neurons. In trisomy 21 fetal neurons, voltage clamp studies revealed decreased activation time constants for outward potassium currents. Additionally,fast TTX-sensitive and slow TTX-insensitive sodium currents could be identified, the latter accounting for 90% of the total charge moving across the membrane. No alterations in maximal conductances were observed. The slow sodium component had slowed deactivation kinetics. Inactivation curves for both fast and slow currents were shifted 10 mV in the depolarizing direction in trisomy 21 neurons, resulting in a greater number of sodium channels available for activation.